Dr/ Ragaa Salama 1

insulinObjectives• Describe the chemical structure of insulin and

the steps of its synthesis.• Describe the mechanisms of storage, secretion,

transport, degradation and excretion of insulin.• Explain the mechanism of action of insulin.• List the effects of insulin on metabolism and

growth..

Dr/ Ragaa Salama 2

insulinObjectives• Describe the chemical structure of insulin and

the steps of its synthesis.• Describe the mechanisms of storage, secretion,

transport, degradation and excretion of insulin.• Explain the mechanism of action of insulin.• List the effects of insulin on metabolism and

growth..

Dr/ Ragaa Salama 3

Chemical structure of insulin

S

S S

S

S

S

-chain

-chain

Insulin

-Insulin is a peptide hormone. -composed of 51 amino acid .-made up of 2 chains of aa, one is 21 aa & one with 30 aa.-3 disulfide bonds .-Zinc forms complex with insulin and proinsulin-It is produced in the islets of Langerhans in the pancreas-effects on both metabolism and several other body systems

Dr/ Ragaa Salama 4

Synthesis of Insulin

-An RNA transcript is translated → preproinsulin protein, → passes through ER →

removal of the signal sequence → formation of 3 disulfide linkages → proinsulin .-it is activated by cleavage and release of the C-peptide, leaving two disulfide linked chains (30

and 21 aa’s) as the mature insulin molecule by specific peptidases and carboxpepidase.-It is stored in granules in the cytoplasm.

Dr/ Ragaa Salama 5

Storage as granules in the cytoplasmor secretory vesicle

post translation modification

Dr/ Ragaa Salama 6

Insulin Secretion• The human pancrease secrets 40-50 units of insulin daily• Factors that ↑ insulin secretion1- glucose : Fasting blood glucose level (60-100mg/dl), the max

response at 300-500 mg/dl.2- Hormonal factors: GH, cortisol, placental lactogen, estrogen,

progesterone ↑ insulin secretion. -Epinephrine → fasting, stress, trauma, and vigorous exercise →

release signals energy utilization → ↓ insulin secretion as insulin stimulates energy storage.

3-Drugs: sulfonylurea, tolbutamide.4-Certain amino acids → stimulate insulin secretion.5-Gastric inhibitory polypeptide (GIP), a gut hormone released after

the ingestion of food → onset of insulin release

Dr/ Ragaa Salama 7

Blood Glucose and Insulin Release• In b-cells, glucose at

elevated levels → Glu-6-P by glucokinase → glycolysis

• Increased glycolysis causes calcium entry → release of insulin

• → reduces blood sugar → slowing insulin release →A perfect feedback system,

Dr/ Ragaa Salama 8

Release• Insulin is released as blood glucose concentrations

rise.• Glucose enters beta cells

and is metabolized to form ATP.

• Increased ATP levels → K+ channels to close, → K+ ions build up and depolarize the cell.

• → activates Ca+2 channels,and Ca+2 ions flow in → triggering the granules to release insulin by exocytosis.

Dr/ Ragaa Salama 9

Transport• When released, insulin molecules attach to

transmembrane receptors outside muscle and fat cells → activate IRS-1 (IRS-1-2,3,4 )proteins inside the cells.

• IRS-1 proteins stimulates glucose transporter molecules, GLUT4, outside the cells

→ taking in glucose.

Dr/ Ragaa Salama 10

Insulin receptor (tetrameric complex)

Insulin

Cellmembrane

Insulin binding siteKinase active site

OHOHOHHO

OP

Phosphorylation

ATP ADPOP

OPPO

Kinase active site opened by induced fit

-2 types of subunits, 2α, 2β subunits, - α -subunit insulin binds, -β -subunit, spans the membrane and protrudes into the cytosol -Insulin receptor is tyrosine kinase .-The kinase activity of insulin receptor is essential to its biological activity- Specific amino acids are found to be binding sites.Once insulin binds to the receptor, 2 β-subunits linked by disulfide bonds are sent through the pore to activate other processes.

Dr/ Ragaa Salama 11

• Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).

Dr/ Ragaa Salama 12

• Insulin and Glucagon are the main players to maintain adequate & normal blood glucose level

Insulin ≠ anti-insulin

Dr/ Ragaa Salama 13

Degradation• Insulin half life is 3-5 min• In liver, kidney , placenta• By 2 enzymes :- protease (insulinase) enzyme

specific for insulin degradion• Glutathione-insulin transhydrogenase → ↓ disulfide

bond• Degradation normally involves endocytosis of the

insulin-receptor complex followed by the action of insulin degrading enzyme.

• Most insulin molecules are degraded by liver cells 50%.

Effect of insulin• On membrane transport• On glucose utilization• On glucose production• On glucose metabolism• On lipid metabolism• On protein metabolism• On cell replication

Dr/ Ragaa Salama 14

Dr/ Ragaa Salama 15

Effects• Control of cellular intake of glucose in muscle and adipose tissue

(about ⅔ of body cells). • Increase of DNA replication and Modification of the activity of

numerous enzymes. • The actions of insulin on cells include:• ↑ glycogen synthesis. • ↑ fatty acid synthesis ↑ lipogenesis in adipose tissue from

triglycerides • ↑ protein synthesis via control of amino acid uptake. • ↓ proteolysis – decreasing the breakdown of protein. • ↓ lipolysis – forces reduction in conversion of fat cell lipid stores into

blood fatty acids; lack of insulin causes the reverse. • ↓ gluconeogenesis. • ↑ potassium uptake by absorbing serum potassium• relax of arterial muscle wall → increasing blood flow, especially in

micro arteries

On membrane transport

- Insulin enter the cells by carrier mediated facilitated diffusion. by translocating the glucose transporter from the cytosol (where it resides in the absence of insulin) to the cell surface, in response to insulin.

-Glucose transporter (a membrane protein that carries out glucose)

1-4 (GLUT1-4).GLUT1 → brainGLUT2 → liver (gluokinase)GLUT4 → adipose tissue, cardiac ms, skeletal ms Insulin stimulates glucose uptake into muscle and adipose cells,

Dr/ Ragaa Salama 16